This invention relates to a pharmaceutical composition and to a method for the local administration thereof for the purpose of treating endometriosis, treating infertility, and improving fertility.
Endometriosis is a condition in which tissue identical with or resembling the lining of the uterus is present in abnormal places, i.e., outside the uterus. Mainly affecting gynecological and other lower pelvic organs, endometriosis often is accompanied by symptoms of painful uterine cramping (dysmenorrhea), pelvic pain, and infertility. The relatively low incidence of endometriosis, the completely unknown time course of its development, and the invasive nature of diagnostic procedures together present a difficult landscape for studying possible prevention of endometriosis.
Classic treatments of endometriosis have been shown to result in a significant decrease in the size (but not disappearance) of endometriotic lesions and in reduction of pain; however, these treatments typically attempt to mimic either menopause or pregnancy, thereby also blocking ovulation. Because traditional treatments of endometriosis consequently prevent pregnancy by blocking ovulation, it would be a great benefit to be able to use treatments that do not interfere with the normal menstrual cycle.
The menstrual cycle can be divided into three characteristic phases based on uterine contractility: the early follicular phase, the late follicular phase, and the luteal phase. During the early follicular phase, uterine contractions are predominately antegrade, propagating from the fundus to the cervical end of the uterus. This pattern of contractility is instrumental for the forward emptying of uterine content (menses). At this phase of the menstrual cycle, uterine contractions typically are perceived by the female and may present a miniature replica of the expulsive contractions of labor. On occasion, these uterine contractions can become so painful as to interfere with daily routines, perhaps requiring medication and/or time off from regular daily obligations. Such painful contractions are termed dysmenorrhea.
The late follicular phase is characterized by predominately retrograde (cervix to uterus) contractions. These play a role in the rapid transport of sperm from the cervical area to the distal end of the tubes where fertilization takes place. Contractions during the late follicular phase are notoriously painless.
The luteal phase is signified by progesterone-induced uteroquiescence with possibly low-amplitude, bi-directional contractions that originate from both ends of the uterus and meet in the middle area. These bi-directional contractions may help in properly positioning the developing embryo in the mid-section of the uterine cavity, where implantation is most likely to take place.
Recent studies have linked endometriosis with dyskinetic patterns of uterine contractility during the female menstrual cycle. Salamanca, A., Beltran, E., Subendometrial Contractility in Menstrual Phase Visualized by Transvaginal Sonography in Patients with Endometriosis. Fertil. Steril., 65:193-95 (1995). Analogy to other forms of smooth muscle dyskinesia (such as irritable bowel syndrome) suggests that alteration of uterine contractility associated with endometriosis is hyperkinetic in type. Sanfilippo, J. S., Wakim, N. G., Schikler, K. N., Yussman, M. A., Endometriosis in association with uterine anomaly, Am. J Obstet. Gynecol. 1986; 154:39-43.
Specifically, hyperkinetic uterine contractions associated with endometriosis may impede the proper antegrade emptying of menstrual blood that normally occurs during the early follicular phase of the menstrual cycle. Normally, menstrual blood empties from the uterus in the direction of the vagina; however, abnormal uterine contractions may cause menstrual blood to chaotically exit the uterus through all openings, including the Fallopian tubes (due to the high-pressure environment of the uterine cavity). This would result in an increase in retrograde bleeding. Retrograde bleeding would ultimately be one of the factors fueling the development of endometriotic implants through direct seeding with debris of endometrial tissue and activation of a chronic inflammatory reaction.
Although it is believed that all women experience some degree of retrograde bleeding during menses (i.e., during the early follicular cycle) at least some of the time. Halme, J., Hammond, M. G., Hulka, J. F., Raj, S. G., Talbert, L. M., Retrograde menstruation in healthy women and in patients with endometriosis, J. Am Ass. Gynecol. Laparoscopists 3 [4 Suppl], S5. 1996, a recent study showed that women suffering from endometriosis had more endometrial debris that displayed a stronger disposition to grow in culture than that obtained from women unaffected by endometriosis. Bulletti, D., Rossi, S., Albonetti, A., Polli, V., De Ziegler, D., Massonneau, M., et. al., Uterine contractility in patients with endometriosis. J. Am. Ass. Gynecol Laparoscopists 3 [4 Supp.], S5, 1996. Another study showed more extensive retrograde transport toward the uterus and tubes of macro-albumin aggregates labeled with Tc-99 (technitium) and placed in the vaginal formix in women with documented endometriosis as compared to unaffected women. Leyendecker, G., Kunz, G., Wildt, L., Beil D., Deininger H., Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility, Hum. Reprod. 1996; 11:1542-51.
Further, alterations of normal retrograde contractions during the late follicular cycle would seem to affect the rapid transport of sperm and affect fertility. This is because contractility along the female tract (uterus and tubes) appears to be the primary motor assuring the rapid transport of sperm from the cervical area to the distal end of tubes where fertilization takes place. Studies show that sperm have been found in the pelvic cavity within minutes of intercourse, well before it could have traveled there on its own steam, thus implicating retrograde uterine contractility in the rapid transport of sperm. Kunz, G., Beil, D., Deininger, H., Wildt, L., Leyendecker, G., The dynamics of rapid sperm transport through the female genitalia tract: evidence from vaginal sonography of uterine peristalsis and hysterosalpingoscintigraphy. Hum. Reprod. 1996; 11:627-32.
xcex2-adrenergic agonists, including, for example, terbutaline, are known to inhibit smooth muscle contractility. Terbutaline and other xcex2-adrenergic agonists exert their pharmacological effects by activation of adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of adenyl cyclase by xcex2-adrenergic agonists increases intracellular levels of cAMP. Cyclic AMP in turn reduces the availability of intracellular free Ca2+, which is required for the activation of myosin light-chain kinase, the enzyme that phosphorylates myosin and thereby allows it to combine with actin to form actomyosin. Lack of Ca2+ results in disruption of the actin-myosin interaction, with resultant inhibition of smooth muscle contractility.
Terbutaline typically is used as a bronchodilator, and has been approved, for example by the United States Food and Drug Administration, for the treatment of asthma. Oral and intravenous terbutaline also have been used as reasonably effective therapies for preterm labor by stopping contractions or postponing delivery. Lyrenas, S., Grahnen, A., Lindberg, B., et. al., Pharmacokinetics of Terbutaline During Pregnancy, Eur. J. Clin. Pharmacol., 29:619-623 (1986); Berg., G., Lindberg C., Ryden G., Terbutaline in the Treatment of Preterm Labour, Eur. J. Respir. Dis., 65:219-230 (1984).
The use of terbutaline in the treatment of dysmenorrhea has been documented. In one study, terbutaline was shown to inhibit myometrial activity, increase blood flow to the uterus, and relieve the pain occurring during uterine contractions accompanying dysmenorrhea. Akerlund, M., Andersson, K. E., and Ingemarsson, E., Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow, and Lower Abdominal Pain in Women with Primary Dysmenorrhoea, Br. J. of Obstet. and Gyn., 83(9): 673-78 (1976). Kullander, S., Svanberg, L., Terbutaline Inhalation for Alleviation of Severe Pain in Essential Dysmenorrhea, Acta Obstet. Gynecol. Scand., 60:425-27 (1981). Although this therapy did provide some efficacy, the treatment was not sufficient for most patients, who had to supplement with other medications for adequate relief. Further, the effect of each spray lasted as little as 1 hour. Id.
Further, using terbutaline and other xcex2-adrenergic agonists for prevention or treatment of dysmenorrhea or premature labor without the normally-expected side effects has been disclosed in Levine, et. al., U.S. Pat. No. 6,126,959. These side effects are discussed further below.
Shortcomings associated with the therapeutic use of xcex2-adrenergic agonists such as terbutaline have limited their utility. For example, they exhibit low bioavailability after oral administration. Although easily absorbed, xcex2-adrenergic agonists exhibit extensive first-pass sulphation. Bioavailability has been estimated at only between 15 and 20%. Concomitant food intake additionally decreases bioavailability by a further 30%. Bricanyl: Scientific brochure, Astra France Laboratories (1993).
Additionally, therapeutic uses of terbutaline have produced significant adverse side effects in the patient, as mentioned above, especially with respect to the cardiovascular system. As a sympathomimetic amine, terbutaline can cause problems in patients with cardiovascular disorders, including arrhythmia, coronary insufficiency, and hypertension. Intravenous administration of terbutaline has been associated with palpitations and peripheral tremors. xc3x85kerlund, M., Andersson, K. F., Ingemarsson, I., Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow and Lower Abdominal Pain in Women With Primary Dysmenorrhea. Br. J. Obstet., Gyncol., 83:673-78 (1976). In addition, intravenous terbutaline has been reported to aggravate preexisting diabetes and ketoacidosis. Terbutaline also may be problematic for patients with hyperthyroidism, diabetes mellitus, or a history of seizures. Other adverse events include tremors, nervousness, increased heart rate, and dizziness. Less frequent adverse effects include headaches, drowsiness, vomiting, nausea, sweating, muscle cramps, and ECG changes. Thus, despite its efficacy, such treatments are often contra-indicated due to the potential adverse consequencesxe2x80x94except when administered as discussed in U.S. Pat. No. 6,126,959, cited above.
The present invention relates to a pharmaceutical composition comprising of (i) a therapeutically effective amount of a xcex2-adrenergic agonist for the purpose of treating endometriosis or infertility, or for improving fertility; and (ii) a pharmaceutically acceptable bioadhesive carrier.
The present invention also relates to a method of treating endometriosis or infertility, or for improving fertility, comprising administering a therapeutically effective amount of a composition comprising a xcex2-adrenergic agonist and a pharmaceutically acceptable bioadhesive carrier locally to the vaginal mucosa of a patient in need thereof.
The present invention also relates to a method of treating endometriosis or infertility, or for improving fertility, comprising administering a therapeutically effective amount of a composition comprising a xcex2-adrenergic agonist without producing detrimental blood levels of the xcex2-adrenergic agonist.